This is the resubmission of a Competitive Renewal application of a parent RO1 whose primary goal was to understand how the structural design features of the human Triceps Surae Complex define its functional properties in vivo. Development of novel devices and imaging techniques allowed non-invasive in-vivo measurement of critical anatomical features that affect function. These consistently revealed heterogeneous strain occurring along the aponeurosis, tendon and muscle fascicles and variation of mechanical gear ratio along the length of the muscle. Subsequent finite element modeling based on these data clearly demonstrated that current models of human neuromuscular in vivo function are inadequate. It is now evident that complex intramuscular mechanics play a critical role in the muscle forces generated in active muscles. To explain the disproportionate decrease in force relative to loss of muscle volume in clinical cases of atrophy and similar pathologies, we hypothesize that: (1) A consistent and reliable specific tension (force per PCSA) of human skeletal muscle can be derived by defining the mechanical heterogeneity of musculoskeletal tissues over multi-scale dimensions;and (2) Changes in selected components of this mechanical complex within and among these musculoskeletal tissues contribute significantly to the loss of muscle force potential as occurs in "disuse" atrophy. 30 normal subjects will be imaged from which 12 with the broadest range of muscle shapes will be chosen for inducement of controlled atrophy by Unilateral Limb Suspension followed by rehabilitation. A highly integrated array of imaging techniques will characterize comprehensively, the multi- component musculoskeletal (MSK) architecture and function of the lower leg, in normal, atrophied and at various stages of recuperation in these subjects and in 8 patients recovering from Achilles Tendon Rupture. Specific Aim (SA)-1 will measure the MSK parameters: (A) 3D volume rendered images of the muscle complex, (B) Distribution of tendon, aponeurosis and intra-muscular connective tissues, (C) Muscle fiber orientation throughout the muscles and (D) total MVC. SA-2 will define the relative contribution to losses of torque due to atrophy-induced changes from: (A) Muscle deformation, (B) Muscle fiber strain, (C) Aponeurosis strain and shear, (D) Tendon excursion and, (E) Calcaneus displacement. (SA-3) Subject-specific image-driven mesh-free (A) Component Level, and (B) Multi- scale, multi-component Systems Level models will be used to predict strain distribution, ankle joint displacement and total joint force. Predictions of the model as to the sensitivity of the total joint force and other output variables to changes in material properties arising from various stages between normal and atrophied states will be compared with the experimental observations in SA-2. Following the guidelines of PA-07-279, a "multi-disciplinary integrative, systems approach" will be applied "to understand (the) important biological, bioengineering problem" of the complex muscle structure-function interactions. This has far ranging clinical potential for tailored management of patients with musculoskeletal disease such as chronic muscle disuse, muscular dystrophy and spasticity. PUBLIC HEALTH RELEVANCE: In the parent R01 of this Competitive Renewal, we investigated the structural and functional design features of a typical musculoskeletal system that could account for apparent paradoxes in current descriptions of muscle behavior. The present proposal investigates the possibility that heterogeneity in structure and physiology of the system may be the primary reason for less than conventionally expected forced output from the limb and its drastic reduction after atrophy. Such basic physiological understanding of the complex muscle structure-function interactions has far ranging clinical potential for the management of subjects with musculoskeletal disease such chronic muscle disuse, muscular dystrophy and spasticity.